Role Of KRAS Mutations Research Articles

Bladder adenocarcinoma: Role of KRAS mutations in differentiating primary versus metastatic

Bladder adenocarcinoma: Role of KRAS mutations in differentiating primary versus metastatic

Targeted degradation of KRAS protein in non-small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles.

The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, "undruggable" KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the "undruggable" KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.

KRAS as a Prognostic and Predictive Marker in Metastatic Non-Small Cell Lung Carcinoma: A Systematic Review.

Metastatic non-small cell lung cancer (NSCLC) poses a significant clinical challenge, prompting a focused investigation into the role of KRAS mutations in prognosis and treatment response. Targeted therapies offer promising avenues for intervention, motivating a comprehensive analysis of existing evidence. Conducted in June 2023, our review delved into MEDLINE (Medical Literature Analysis and Retrieval System Online), Embase, Scopus, and the Cochrane Register of Controlled Trials. Rigorous inclusion and exclusion criteria guided the selection of 12 articles, comprising two randomized controlled trials (RCTs) and 10 observational studies. Multiple investigators independently executed data extraction, evaluating prognostic factors (overall and progression-free survival) and predictive outcomes (treatment and objective response). The Newcastle-Ottawa Scale (NOS) and modified Jadad scores were used for study quality assessment of observational studies and RCTs, respectively. From an initial pool of 120 articles, the 12 selected studies, spanning 2013 to 2022, encompassed 2,845 metastatic NSCLC patients. KRAS mutations, particularly the G12C variant, emerged as a pivotal factor influencing treatment response. Notably, KRAS wild type patients displayed enhanced responses to platinum-based chemotherapy, while those with KRAS mutations exhibited favourable outcomes with immune checkpoint inhibitors (ICIs). The role of KRAS mutations as prognostic indicators in metastatic NSCLC is underscored by this systematic review, with implications for both survival and treatment response. The discernment between KRAS wild type and mutant patients offers insights into tailored therapeutic strategies, with platinum-based chemotherapy and immune checkpoint inhibitors emerging as context-dependent options. Nevertheless, more research is required to solidify the predictive role of KRAS and explore the efficacy of KRAS inhibitors and other targeted therapies, paving the way for refined and personalized interventions in the management of metastatic NSCLC.

The Role of KRAS Mutation in Colorectal Cancer-Associated Thrombosis

Venous thromboembolic events (VTE) are common in patients with colorectal cancer (CRC) and represent a significant contributor to morbidity and mortality. Risk stratification is paramount in deciding the initiation of thromboprophylaxis and is calculated using scores that include tumor location, laboratory values, patient clinical characteristics, and tumor burden. Commonly used risk scores do not include the presence of molecular aberrations as a variable. This retrospective study aims to confirm the link between KRAS-activating mutations and the development of VTE in CRC. A total of 166 patients were included in this study. They were split into two cohorts based on KRAS mutational status. We evaluated the frequency and mean time to VTE development stratified by the presence of KRAS mutations. Patients with mutant KRAS had an odds ratio (OR) of 2.758 for VTE compared to KRAS wild-type patients, with an increased risk of thrombosis being maintained in KRAS mutant patients even after adjusting for other known VTE risk factors. Taking into account the results of this study, KRAS mutation represents an independent risk factor for VTE.

Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47.

KRAS is one of the most frequently activated oncogenes in human cancers. Although the role of KRAS mutation in tumorigenesis and tumor maintenance has been extensively studied, the relationship between KRAS and the tumor immune microenvironment is not fully understood. Here, we identified a role of KRAS in driving tumor evasion from innate immune surveillance. In samples of lung adenocarcinoma from patients and Kras-driven genetic mouse models of lung cancer, mutant KRAS activated the expression of cluster of differentiation 47 (CD47), an antiphagocytic signal in cancer cells, leading to decreased phagocytosis of cancer cells by macrophages. Mechanistically, mutant KRAS activated PI3K/STAT3 signaling, which restrained miR-34a expression and relieved the posttranscriptional repression of miR-34a on CD47. In 3 independent cohorts of patients with lung cancer, the KRAS mutation status positively correlated with CD47 expression. Therapeutically, disruption of the KRAS/CD47 signaling axis with KRAS siRNA, the KRASG12C inhibitor AMG 510, or a miR-34a mimic suppressed CD47 expression, enhanced the phagocytic capacity of macrophages, and restored innate immune surveillance. Our results reveal a direct mechanistic link between active KRAS and innate immune evasion and identify CD47 as a major effector underlying the KRAS-mediated immunosuppressive tumor microenvironment.

Energy balance-related factors and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status

IntroductionKRAS mutations (KRASmut), PIK3CAmut, BRAFmut, and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status.MethodsInformation on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRASmut; PIK3CAmut; BRAFmut; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR).ResultsIn men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CAmut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRASmut colon cancer (p-heterogeneityKRASmut versus all-wild-type+pMMR = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CAmut tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men.ConclusionIn men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer.

Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma.

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

The Role of KRAS Mutations in Cortical Malformation and Epilepsy Surgery: A Novel Report of Nevus Sebaceous Syndrome and Review of the Literature.

The rare nevus sebaceous (NS) syndrome (NSS) includes cortical malformations and drug-resistant epilepsy. Somatic RAS-pathway genetic variants are pathogenetic in NS, but not yet described within the brain of patients with NSS. We report on a 5-year-old boy with mild psychomotor delay. A brown-yellow linear skin lesion suggestive of NS in the left temporo-occipital area was evident at birth. Epileptic spasms presented at aged six months. EEG showed continuous left temporo-occipital epileptiform abnormalities. Brain MRI revealed a similarly located diffuse cortical malformation with temporal pole volume reduction and a small hippocampus. We performed a left temporo-occipital resection with histopathological diagnosis of focal cortical dysplasia type Ia in the occipital region and hippocampal sclerosis type 1. Three years after surgery, he is seizure-and drug-free (Engel class Ia) and showed cognitive improvement. Genetic examination of brain and skin specimens revealed the c.35G > T (p.Gly12Val) KRAS somatic missense mutation. Literature review suggests epilepsy surgery in patients with NSS is highly efficacious, with 73% probability of seizure freedom. The few histological analyses reported evidenced disorganized cortex, occasionally with cytomegalic neurons. This is the first reported association of a KRAS genetic variant with cortical malformations associated with epilepsy, and suggests a possible genetic substrate for hippocampal sclerosis.

Positive Crosstalk Between Hedgehog and NF-κB Pathways Is Dependent on KRAS Mutation in Pancreatic Ductal Adenocarcinoma.

It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.

Cytology-based Detection of Circulating Tumour Cells in Human Pancreatic Cancer Xenograft Models With KRAS Mutation.

To examine the dynamics of circulating tumour cells (CTCs) in pancreatic cancer (PC), new mouse CTC models from human PC xenografts were developed. Orthotopic (pancreas) and heterotopic (subcutaneous) transplantation models using GFP-tagged SUIT-2 PC cells were prepared. Using a cytology-based CTC detection platform, CTCs and metastasis were compared. The two types of orthotopic models, including the surgical transplantation model and the intraperitoneal injection model, showed a similar pattern of initial pancreatic tumour formation and subsequent development of peritoneal and hematogenous lung metastases. In the heterotopic model, only hematogenous lung metastasis was observed, and the number of CTCs and lung metastases was higher than that of the orthotopic model. Furthermore, KRAS mutation (G12D) was detected in CTCs. These orthotopic and heterotopic models clearly differ in terms of the pattern of metastasis and CTCs and therefore, would be useful PC models to investigate the effect of drug-therapy on CTCs and the role of KRAS mutation.

Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer (NSCLC) patients.

e21080 Background: The prognostic and predictive role of KRAS mutations and gene copy number aberrations (CNA) in early stage NSCLC is unclear. In this study, we characterize the prognostic effect of KRAS mutation status and concomitant CN gain in early stage NSCLC, and determine the ability to predict survival benefit from adjuvant chemotherapy. We hypothesize that concomitant KRAS mutations and CN gain will be prognostic of worse survival compared to KRAS mutations alone. Methods: Clinical and genomic data from The LACE (Lung Adjuvant Cisplatin Evaluation)-BIO consortium was utilized. CNA were categorized as Gain or Neutral (Neut)/Loss; mutation status was defined as wild type (WT) or mutant (MUT). WT+Neut/Loss (reference), WT+Gain, MUT+Gain and MUT+Neut/Loss groups were compared in all patients and the adenocarcinoma subgroup. Primary endpoint was lung-cancer-specific survival (LCSS); secondary endpoints were DFS and OS. Survival curves were assessed using Kaplan-Meier and log-rank tests. Concomitant KRAS CNA and mutation status was correlated to endpoints using a Cox proportional hazards model stratified by trial and adjusted for treatment, age, gender, histology, WHO performance status, surgery type, tumor and nodal stage. A treatment-by-variable interaction was added to evaluate predictive effect. Results: 946 (399 adenocarcinoma) patients had complete KRAS mutation, CNA and clinical data: 41 (30) MUT+Gain, 145 (99) MUT+Neut/Loss, 125 (16) WT+Gain, 635 (254) WT+Neut/Loss. There was a negative prognostic effect of KRAS MUT+Neut/Loss for LCSS (HR = 1.32 [1.01-1.71]) on univariable analysis, and to a lesser extent after adjusting for covariates (HR = 1.28 [0.97-1.68]). A similar non-significant trend was observed in KRAS MUT+Gain patients for LCSS (HR = 1.34 [0.83-2.17]), DFS (HR = 1.34 [0.86-2.09]) and OS (HR = 1.59 [0.99-2.54]). There was no significant predictive effect in the overall population; however, a potential predictive effect of KRAS for OS was seen in the adenocarcinoma subgroup (interaction p = 0.046). KRAS MUT+Gain was associated with a beneficial effect of chemotherapy on DFS (HR = 0.33 [0.11-0.99], p = 0.048), with a non-significant trend also seen for LCSS (HR = 0.41 [0.13-1.33]) and OS (HR = 0.40 [0.13-1.26]). Conclusions: A small prognostic effect of KRAS mutation was identified for LCSS. A potential predictive effect of concomitant KRAS mutation status and CNA was observed for DFS in adenocarcinoma patients. These results could be driven by the small number of patients and require further validation.

Incidence of venous thromboembolism in patients with colorectal cancer according to oncogenic status.

There are conflicting data regarding the role of KRAS mutation on the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients. Moreover, the role of other biomarkers such as NRAS or BRAF has not been studied. To analyze the incidence of VTE in a cohort of patients with CRC based on KRAS, NRAS, and BRAF status. We performed a retrospective review of patients with unresectable locally advanced and metastatic CRC (mCRC) and known KRAS/NRAS/BRAF status, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain). The primary outcome was VTE defined as any venous thromboembolic event that occurred either 6months before or at any time after the diagnosis of CRC. The biomarker status (KRAS, NRAS, and BRAF) and other predictors of thrombosis were collected. One hundred and ninety-four patients were identified and included in the analysis. Forty-one patients (21.1%) experienced VTE. The incidence was 19.1% in RAS-mutated patients, 28.6% in BRAF-mutated patients and 21% in triple wild-type patients (p = NS). In multivariate analysis, ECOG ≥ 2 was the only independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). In our study, biomarkers have not been associated with an increased risk of VTE in CRC patients. A high incidence of VTE in BRAF-mutated patients has been observed and should be explored in further studies.

Abstract 2079: Enhanced potency of the polymeric fluoropyrimidine CF10 to KRAS-mutant colorectal cancer cells

Abstract Background: Mutant KRAS is a key stratification factor in determining colorectal cancer (CRC) treatment. Nearly 50% of CRC tumors have KRAS mutations and these patients are unlikely to respond to anti-EGFR therapy. 5-fluorouracil (5-FU)-based chemotherapy is the preferred treatment for CRC patients with KRAS mutations; however, response rates remain very low for patients with advanced disease. Further, a sub-set of patients treated with 5-FU-based regimens suffers from serious side effects resulting from RNA-directed effects that do not contribute to the anti-cancer activity. We are developing polymeric fluoropyrimidines, such as CF10, to treat CRC more effectively and with reduced side effects. CF10 is >300-fold more potent than 5-FU across the NCI 60 cell line screen with particularly strong potency to KRAS-mutant CRC cells. We investigate the role of KRAS mutation on CF10 and 5-FU response as part of an overall effort to determine if CF10-based regimens can more effectively treat CRC patients for whom 5-FU-based regimens are currently the preferred treatment option. Methods: HKe3-wtKRAS and HKe3-mtKRAS were generated from HCT-116 human CRC cells (ATCC) by transfection with the pMSCVpuro vector encoding HA-tagged mutant or wild-type KRAS. Cytotoxicity was determined using an Alamar blue assay. Thymidylate synthase (TS) inhibition was evaluated by detecting ternary complex formation by Western blot and using a TS activity assay. Topoisomerase 1 cleavage complex (Top1cc) was evaluated using a RADAR assay and by immunofluorescence. DNA double strand breaks were detected by IF for γH2AX. Results: CF10 is highly potent to CRC cells regardless of KRAS mutation status. In isogenic cell lines that differ only in KRAS, CF10 is more potent to KRAS-mutant relative to wild type cells. The improved potency of CF10 relative to 5-FU and increased sensitivity of KRAS-mutant cells is enhanced for cells grown in 3D culture. CF10 cytotoxicity is mediated by TS inhibition and Top1cc formation that induces DNA DSBs and activates apoptosis. In vivo, CF10 displays significantly improved anti-tumor activity relative to 5-FU in HCT-116 orthotopic tumors and causes minimal systemic toxicity. Conclusions. KRAS mutation confers increased sensitivity to the DNA-directed fluoropyrimidine CF10. The overall mechanism of CF10 cytotoxicity to CRC cells is similar in both KRAS-WT and KRAS-MT CRC cells and involves TS inhibition, and misincorporation of FdU into DNA followed by generation of Top1-mediated DNA DSBs. Our studies indicate FP polymers are likely to be effective in CRC regardless of KRAS-mutation. The increased sensitivity of KRAS-mutant CRC to CF10 together with the very low systemic toxicity indicates that CRC patients currently being treated with 5-FU-based therapy could more effectively be treated with CF10-based regimens. Citation Format: William H. Gmeiner, Mandira Manandhar, Amanda M. Hinds, Julija Holmes, Pierre Vidi, Toshiyuki Tsunoda, Senji Shirasawa. Enhanced potency of the polymeric fluoropyrimidine CF10 to KRAS-mutant colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2079.

The prognostic value of KRAS mutation in locally advanced rectal cancer.

e15090 Background: The prognostic value and prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC). Methods: We identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status.Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival. Results: Of the 784 eligible patients, 506 and 278 were KRAS negative (KRAS-) and KRAS positive (KRAS+). Median survival was 63.6 months and 76.3 months for KRAS+ and KRAS-patients, with propensity adjusted 3 and 5-year survival of (79.9% vs. 83.6%) and (56.7% vs 61.9%) respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS+ disease was associated with poorer survival on unadjusted and propensity adjusted multivariable analyses (Table). Conclusions: Our analysis of KRAS+ LARC suggest that KRAS+ disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted. [Table: see text]

Role of KRAS Mutations in Patients with Metastatic Colorectal Cancer Who Receive Regorafenib Plus FOLFIRI as a Salvage Therapy

目的：本研究的目的在於評估KRAS基因的角色在接受regorafenib及irinotecan劑量調整過的FOLFIRI當作救援治療的轉移性大腸直腸癌病人。方法：以單一醫學中心，從2013年10月至2017年6月，總共收錄了21位病人。回顧性的記錄其臨床特徵及以regorafenib及irinotecan劑量調整過的FOLFIRI當作救援治療的療效。其無進展生存期、總生存期依據KRAS基因做出分組分析。結果：經過10.0個月(1.3-38.6個月)中位數追蹤時間，全部病人的中位數無進展生存期及總生存期分別為7.0及10.0個月。疾病控制率為61.9%，其中包含有9.5%的病人疾病程度為部分改善及52.4%為穩定疾病。在KRAS基因野生型及突變型之間，兩個族群的中位數無進展生存期(野生型7.0個月對比突變型5.5個月，p值等於0.494)及中位數總生存期(野生型13.0個月對比突變型9.5個月，p值等於0.249)。兩組病人的性別、年齡、UGT1A1基因型、irinotecan劑量、治療反應、疾病控制率及手足症候群發生率亦均無統計學上的顯著差異。結論：針對轉移性大腸直腸癌病人以regorafenib及irinotecan劑量調整過的FOLFIRI的合併治療可以得到較好的疾病控制率及較長的無進展生存期及總生存期。而KRAS基因野生型的轉移性大腸直腸癌病人在接受此合併療法後顯示出無統計學上差異但仍有較好的治療趨勢。

Role of KRAS Mutations in Patients with Metastatic Colorectal Cancer Who Receive Regorafenib Plus FOLFIRI as a Salvage Therapy

Role of KRAS Mutations in Patients with Metastatic Colorectal Cancer Who Receive Regorafenib Plus FOLFIRI as a Salvage Therapy

AURA3 trial: does Tagrisso (osimertinib) have the potential to become the new standard of care for second-line treatment of patients with EGFR T790M mutation-positive locally advanced or metastatic NSCLC.

Vassiliki A Papadimitrakopoulou speaks to Roshaine Wijayatunga, Managing Commissioning Editor: Dr Papadimitrakopoulou is the Jay and Lori Eisenberg Distinguished Professor of Medicine and Chief of the section of Thoracic Medical Oncology in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas/MD Anderson Cancer Center. Her areas of expertise include design and development of novel therapeutic clinical trials for lung and head and neck neoplasms, personalized genomics-driven lung cancer therapy and translational research and cancer chemoprevention. Her extensive experience in design, development and implementation of translational research in the context of multidisciplinary research teams has led to research funding from National Cancer Institute (NCI), American Society of Clinical Oncology (ASCO) and Department of Defense (DOD) both independently and as a member of a research team in the Head and Neck SPORE program. Currently, she serves as the principal investigator and leads numerous clinical and translational research projects with a focus on the development of biomarker-based targeted therapy to overcome therapeutic resistance in advanced disease and immunotherapy. Most notably, she has led the multidisciplinary clinical and translational research infrastructure dedicated to the treatment of metastatic refractory NSCLC as part of the BATTLE-2 program, designed and developed the first-in-the-world comprehensive genomics-driven umbrella approach in Squamous Lung Cancer, the Lung Master protocol, jointly sponsored by NCI-Cancer Therapy Evaluation Program (CTEP) and Foundation for the National Institutes of Health (FNIH)/industry, aiming at bringing personalized medicine to patients with this disease. She is the Co-PI of an R01 award focusing on the role of KRAS mutations and targeting in lung cancer. She is the lead author or coauthor of over 150 published articles, book chapters and reviews, and numerous abstracts involving cancer therapeutics, prevention and translational research and she has received several awards including the ASCO Young Investigator and Career Development Award. On this R01 application, she will serve as Co-PI, working closely with Roy Herbst (Yale Cancer Center) and Don Gibbons (UT/MD Anderson Cancer Center), building on the recently completed BATTLE-2 program, and capitalizing on both laboratory findings supporting MEK targeted therapy and clinical effectiveness of immunotherapy and their combinations in addressing KRAS mutated lung cancer.

EGFR and KRAS mutational analysis in a large series of Italian non-small cell lung cancer patients: 2,387 cases from a single center.

Activating EGFR mutations are important genetic alterations that have strong therapeutic implications for non-small cell lung cancer(NSCLC) patients. However, the role of KRAS mutations in this process is still under evaluation. Here, we report on the feasibility of a large‑scale EGFR and KRAS mutation analysis in the daily routine of a single center. NSCLCs from 2,387patients were screened for EGFR and KRAS mutations from January 2010 to September 2015. Mutational analyses were performed in a single laboratory using single strand conformation polymorphism(SSCP)-Sanger sequencing and matrix‑assisted laser desorption ionization‑time of flight(MALDI‑TOF) on Sequenom platform for EGFR and pyrosequencing for KRAS. Activating EGFR mutations were found in 14.1% of all tumors, whereas KRAS mutations were found in 30.5% of all tumors. Direct sequencing showed analyzable cytological, small biopsy and surgical specimen percentages of 90.3, 90.9and98.1%, respectively, whereas the MALDI‑TOF platform showed analyzable cytological samples, small biopsies and surgical specimens percentages of 94.6, 95.7and96.9%, respectively. The mean analytical turnaround times(TAT) were 4and3days for direct sequencing and the MALDI‑TOF platform, respectively. Our results confirm that small biopsy or cytological samples can be used for reliable EGFR and KRAS mutation testing and indicate that adopting the MALDI‑TOF platform reduces the rate of missed samples among the samples. Moreover, the 3-day analytical TAT of the MALDI-TOF multi-target technique is appropriate for clinical management and reduces the overall treatment decision time.

Role of KRAS mutation as predictor of pathologic response after neoadjuvant chemoradiation therapy for rectal cancer.

Individual patient response to neoadjuvant treatment is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to evaluate the effect of KRAS mutation on outcomes following neoadjuvant chemoradiation therapy (CRT) for rectal cancer. A total of 76 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery. In every patient tumor-related features and outcome results were considered for analysis and correlation with KRAS mutations. Forty-four patients (58%) obtained a downstaging after CRT, and in 7 patients (9%) a complete pathological response was found. Twenty-six (33%) mutations of KRAS were found in 26 patients. Nineteen mutations (73%) were located in codon 12, 6 in codon 13(23%) and 1 in codon 61. T-level downsizing and tumor downstaging showed no significant association with KRAS mutation status, except for mutation of codon 13(G13D). No correlation between cancer-associated mortality following CRT and surgery and KRAS mutation was observed. No correlation between pelvic recurrence and KRAS mutation was observed. KRAS mutation also failed to correlate with disease-free survival. No patients with a pCR had a local or distant failure. There appears to be no significant difference in pCR, tumor down-staging, T-downsizing or effects on cancer-associated mortality, overall survival and disease-free survival in patients with KRAS mutations except for patients with KRAS codon 13 mutations that seem to be resistant to neoadjuvant CRT and less likely to achieve a pCR.

K-ras mutational status and its clinical implications in Korean colorectal cancer patients.

641 Background: The incidence of K-ras mutation of exon 2 was reported between 30-40% in colorectal cancer, and it is well known predictive biomarker for EGFR monoclonal antibody. However, its prognostic role has not been defined so far, especially in Eastern country. Methods: From January 2007 to September 2013, patients who were diagnosed as colorectal cancer and examed K-ras exon 2 mutation in Saint Vincent’s hospital were retrospectively reviewed. Results: Among 436 patients, 343 patients with sufficient clinical information were analyzed. The median follow up period was 13.0 (0.2-94.8) months. The incidence of K-ras mutation was 37.9% (codon 12 mutation: 28.6%, codon 13 mutaiton: 9.0%, both: 0.3%). Codon 12 p.G12D was most frequent (52.3%), and codon 13 p.G13D was the next (22.3%). The presence of K-ras mutation was associated with old age (p=0.038), female gender (p=0.034), lesser nodal involvement (p<0.001), but not related to stage, tumor site, and histology. There is no significant clinical differences between codon 12 and 13 mutations. The recurrence free survival in patients who received curative resection was worse in patients with K-ras mutation (p=0.001). The prognostic role of K-ras mutation was more prominent in colon cancer, while it lost its prognostic significance in rectal cancer. Conclusions: The prognostic role of K-ras mutation was different according to primary tumor sites in colorectal cancer.